The incidence of malignant melanoma is rising faster than that of any other cancer, yet treatment options for patients with advanced disease remain limited. The development of agents that inhibit tumor vascularization represent a novel approach to the treatment of these cancers. Tumors secrete a number of factors that stimulate the formation of new vessels, and two important molecules in this regard are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Given this fact, we feel it is logical to explore combinations of anti-angiogenic drugs in an attempt to achieve greater anti-tumor activity. We have received NCI approval to conduct a randomized phase II trial of recombinant anti-human VEGF (Bevacizumab) alone or in combination with low-dose interferon-alpha (IFN-a) (Aim 1). Bevacizumab prevents the binding of VEGF to receptors on endothelial cells and has shown activity in colon, breast, lung, and prostate cancer. Low-dose IFN-a inhibits the elaboration of bFGF and has been successfully used to treat infantile hemangiomas. We hypothesize that co-administration of Bevacizumab and low-dose IFN-a will lead to maximal inhibition of new vessel formation in patient tumors and that this will result in improved response rates and increased time to disease progression. Patients with metastatic malignant melanoma will receive Bevacizumab at 10 mg/kg IV every 14 days and will be randomized to receive either no additional treatment or concurrent IFN-a at 1 MU/m2 SC daily. In Aim 2, we will conduct a series of correlative studies designed to elucidate the mechanisms that contribute to the anti-tumor actions of these drugs. Patient blood samples will be drawn just prior to the administration of Bevacizumab and procured for serum and peripheral blood mononuclear cells. Serum levels of VEGF and bFGF will be analyzed by ELISA. In addition, we will perform tumor biopsies prior to the initiation of therapy and immediately following the 6th dose of Bevacizumab. Tumors will be analyzed for vascularity (CD31 and CD34), levels of angiogenic factors, as well as the presence of apoptotic cells. Given the prevalence of accessible tumor deposits in melanoma patients, we feel we will be able to successfully biopsy a majority of patients enrolled in this study. This approach represents one of the few trials to employ combinations of anti-angiogenic drugs and an aggressive plan for tumor sampling. Information gained from this trial will help us to understand the mechanism of action of anti-angiogenic drugs and help us to plan future studies in melanoma and other solid tumors.